1. Treating Tobacco Dependence
Stacy Seikel, MD
Board Certified Addiction Medicine
Board Certified Anesthesiology

2. Cigarettes
Tobacco smoke – complex mixture of 4,000 chemicals with over 60 known carcinogens
Cigarette smoking – responsible for 1 in 5 deaths in USA (>400,000 deaths/year)
1965 to 1999 – Decline in smoking rate, 41% to 22.8%
Recent decrease in youth smoking

3. What Is Tobacco Dependence?
Nicotine Dependence ≠
Tobacco Dependence

4. Medical Consequences of Nicotine Dependence
Negligible
Chronic nicotine medication use after stopping tobacco use likelihood of cardiac events

5. Medical Consequences of Tobacco Dependence
Massively Overwhelming!!

6. Cigarette smoking is the chief avoidable cause of death in our society

7. Cigarettes Cause
Lung Cancer
COPD
Heart Disease
Other Cancers

8. The Cost of Smoking
442,000 deaths per years caused by smoking – 18%

9. Cigarette Smoking is NOT a Habit

10. What Is Tobacco Dependence?
It Is a
CHRONIC MEDICAL
DISEASE.

11. FDA Drug Abuse Advisory Committee – June 9, 1997
“Tobacco dependence is a…[serious,] chronic, relapsing, life-threatening illness, that requires…long-term medical management.”
Curtis Wright, MD, PhD
Deputy Director, Div. of anesthetics, Critical Care, &
Addiction Drug Products
Food & Drug Administration

13. FACTORS UNDERPINNING TOBACCO DEPENDENCE
Psychological Dependency
Nicotine Addiction

14. Factors that perpetuate smoking
Cheap “high”
Nicotine is a stimulant—releases HGH, epinephrine, serotonin, norepinephrine
Intravenous nicotine is indistinguishable from amphetamine for the first 10 minutes
Very rapid neuroadaptation (tolerance) to nicotine; smokers generally discount the stimulant effects

15. Factors that perpetuate smoking
Withdrawal symptoms
Irritability, agitation, anxiety, hunger, difficulty concentrating
Relieved within a few seconds by smoking a cigarette
Symptoms are constant, uncomfortable, socially disruptive
Repeated episodes of withdrawal and relief of withdrawal induce avoidance of withdrawal

16. Factors that perpetuate smoking
Relief of dysphoric feelings
Nicotine affects the ventral tegmental area and mesolimbic system as do most other drugs of addiction
Nicotine often substitutes for other (less socially acceptable) drugs
Very rapid CNS effects due to inhalation
Relief of withdrawal symptoms (anxiety) can be confused with relief of dysphoria (anxiety)

17. Factors that perpetuate smoking
Conditioned responses (“triggers”): Smoking is associated with a wide range of activities
Drinking alcohol, eating a meal, drinking coffee
Sexual activity
Completion of a project, escape from danger, end of the workday
Celebrations
Driving a car
Waiting
Seeing others smoke; smelling tobacco or smoke

18. ADDICTED SMOKERS Some are minimally dependent
Others are severely dependent
Genetic heritage affects dependence

19. ADDICTION CIGARETTES 10% not dependent 90% are dependent ALCOHOL

20. Treating Tobacco Dependence
Severe but treatable
70% of smokers visit a physician and 50% visit a dentist each year
Most smokers want to stop and 46% try to stop each year
Multicomponent therapy

21. Chronic Disease Nature of Tobacco Dependence
Just like asthma, hypertension, or diabetes treatment, clinical deterioration is the rule and to be expected, when tobacco-dependence pharmacotherpy is stopped.

22. Interventionists Counselor Nurse CD Counselor Respiratory Therapist
Psychologist
Physician
Dentist
Dental Hygienist
Nurse Practitioner
Physician Assistant
Occupational Therapist

23. Clinical in Practice Guideline Major Conclusions/Recommendation
Tobacco dependence is a chronic condition
Effective treatments exist and all tobacco users should be offered treatment
Healthcare systems must systematize identification, documentation, and treatment of every tobacco user
Brief interventions are effective, but there is a strong dose response
Counseling effective
Pharmacotherapy is effective, and at least one should be prescribed
Treatments are cost-effective

24. Treating Tobacco Dependence Principles of Treatment
Behavioral
Addictive disorders
Pharmacologic
Relapse prevention

25. Treating Tobacco Dependence Healthcare Professional’s Role
Identify the smoker
Personalize the risks of smoking and benefits of stopping
Encourage patient to set stop date
Provide and monitor pharmacologic therapy
Follow-up and ongoing support
Referral

26. FDA-Approved Tobacco-Dependence Medications
CONTROLLER MEDICATIONS
Bupropion SR ((Zyban, Wellbutrin SR)
Nicotine Patch – OTC
Varenicline (Chantix)
RELIEVER MEDICATIONS
Nicotine Inhaler
Nicotine Nasal Spray
Nicotine Polacrilex Gum (Nicorette) – OTC
Nicotine Polacrilex Lozenge (Commit) – OTC
Nicotine-8-Cyclodextrin – OTC
Sublingual tablet

27. NICOTINE MEDICATION SAFETY
Nicotine does not cause lung cancer
Tobacco smoke does
Nicotine does not cause COPD
Nicotine does not cause acute MI
Nicotine does not cause acute vascular injury

28. Benefit of Prescribing At Least One Medication – Evidence-Based
All FDA-approved medications suppress nicotine withdrawal signs and symptoms
Any one medication probability of stopping smoking
2-3 x
During medication treatment period
1 year after medication treatment-end

29. Benefit of Prescribing Two Medications – Evidence-Based
Any pair of FDA-approved medications further probability of stopping smoking
50-100% over any one, effective medication
During medication treatment period
1 year after medication treatment-end
Do not give Chantix with nicotine replacement therapy

30. Nicotine Liquid in its native state
Distilled from burning tobacco and carried on tar droplets
Free (unprotonated) nicotine crosses biological membranes, therefore pH dependent
Inhalation → peak arterial concentrations 2-4 x venous concentrations
Extensive first pass hepatic metabolism
Half-life 120 minutes

31. Treatment Pharmacotherapy
First line
Nicotine gum
Nicotine patches
Nicotine nasal spray
Nicotine inhaler
Nicotine lozenge
Bupropion
Varenicline
Second line
Clonidine
nortriptyline

32. Nicotine Patch Therapy Background
Placebo-controlled trials show doubling of stop rates
Growing literature showing a dose response
-50% median replacement with standard dose
Reduced smoking
while using nicotine patch

33. High Dose Patch Therapy Conclusions
High dose patch therapy safe for heavy smokers
Smoking rate or blood continue to estimate initial patch dose
Assess adequacy of nicotine replacement by patient response or percent replacement
More complete nicotine replacement improves withdrawal symptom relief
Higher percent replacement may increase efficacy of nicotine patch therapy

34. High Dose Patch Therapy Dosing Based on Smoking Rate
<10 cpd mg/d
10-20 cpd mg/d
21-40 cpd mg/d
>40 cpd mg/d
2 ppd = 2 patches

35. Nicotine Patch Therapy Clinical Use
Individualize the dose and duration
Base initial dose on smoking rate or blood continine
Usual length of therapy: 6-8 weeks
Return visit or phone call at 1 or 2 week intervals
Adjust dose and determine length of Rx based on response

36. Bupropion Background Monocyclic antidepressant
Inhibits reuptake of norepinephrine and dopamine
May inhibit nicotinic ACH receptor function
Mechanism in helping smokers stop is not clear
May attenuate weight gain in abstinent smokers

37. Bupropion for Relapse Prevention Results
58.8% smoking abstinence at week 7
Relapse rate lower in active group through weeks 12 and 24 but not thereafter
Median time to relapse 156 d (active) vs. 65 d (placebo)
Smoking abstinence 47.7% (active) vs. 37.7% (placebo) through week 78
Weight gain 3.8 and 4.1 kg (active) vs. 5.6 and 5.4 kg (placebo) at weeks 52 and 104

38. Bupropion Summary Dose response efficacy in treating smokers
Attenuates weight gain
May be more effective than nicotine patch therapy
Delays relapse to smoking
Can be prescribed to diverse populations of smokers with expected comparable results

39. Medication strategies
Partial receptor antagonist
Varenicline (Chantix) 39

40. Varenicline Approved May 11, 2006 by FDA (Pfizer)
Partial agonist at the nicotine receptor
High affinity for the α4β2 subtype nicotine receptor
Trade name: Chantix
Derived from natural chemical cytisine, found in the plant “false tobacco”
Foulds (2006) The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. J Clin Pract 60: 571–576 40

41. T ½ excretion = 17 ± 3 hours
Orbach et al (2006) Drug Metabolism and Distribution 41

42. Nicotine receptor Nicotine receptor
Powledge TM (2004) Nicotine as therapy.PLoS Biol 2(11): e404.
Nicotine receptor 42

43. Foulds (2006) J Clin Pract 60: 571–57643

44. N
N = Nicotine 44

45. N 45

46. N
Na+ 46

47. V N
V = Varenicline
N = Nicotine 47

48. N V
V = Varenicline
N = Nicotine 48

49. N V 49

50. N V 50

51. N V 51

52. N V 52

53. N V 53

54. N V 54

55. N V
Na+ 55

56. Varenicline
Partial agonist at the N-acetylcholine site—targets the α4β2 receptor
Reduced craving and withdrawal symptoms
The most common adverse effects included nausea, headache, trouble sleeping, and abnormal dreams
No documentation of serious adverse effects
Pfizer: data on file 56

57. Varenicline Varenicline Continuous abstinence, weeks 9-12 Bupropion
44 %
Bupropion
30 %
Placebo
17.7 %
Gonzales. JAMA 296:47-55 57

58. Varenicline Varenicline Abstinence at 12 months of treatment Bupropion
22.9%
Bupropion
16.1%
Placebo
8.4%
Gonzales. JAMA 296:47-55 58

59. Varenicline-adverse effects
Nausea
Dreams
Insomnia
Varenicline
28%
10%
14%
Bupropion
12.5%
5.5%
22%
Placebo
8.4%
12.8%
Gonzales. JAMA 296:47-55 59

60. Varenicline-study drug discontinuation due to adverse effects
Nausea
All causes
Varenicline
2.6%
8.6%
Bupropion
1.8%
15.2%
Placebo
0.3%
9.0%
Gonzales. JAMA 296:47-55 60

61. Varenicline-adverse effects
One report: exacerbation of symptoms in a patient with schizophrenia
One report: exacerbation of manic symptoms in a patient with bipolar disorder
One report: exacerbation of depression and psychosis in a patient with depression and a FH of bipolar disorder
One report: mixed episode and psychosis in a patient with depression
One report: cataracts 61

62. Varenicline-discontinuation due to adverse effects, 1 year
Placebo
Adverse effects
26%
10%
Lack of efficacy 5%
Protocol deviations 2% 3%
Lost to f/u
15%
Refusal to continue study
16%
All causes
46%
53%
Williams. 23: 62

63. Varenicline-adverse effects
Placebo
Nausea
40% 8%
Dreams
23% 7%
Insomnia
19%
9.5%
Disgeusia
11% 2%
Dizziness 5%
Any adverse effect
96%
83%
Williams. 23: 63

64. Varenicline-cessation
Placebo
Abstinence at week 52
37% 8%
Williams. 23: 64

65. Possible explanations for adverse psychiatric effects
Varenicline is a dangerous drug 65

66. Possible explanations for adverse psychiatric effects
Smoking is a dangerous behavior
Nicotine has a prolonged effect on receptor function, causing profound and long-term alterations in mood, cognition, and behavior
Cessation of nicotine use results in poorly understood, but significant effects on mood, cognition, and behavior
Many of the adverse effects seen in patients using varenicline are due to long-term use of tobacco and nicotine, and nicotine withdrawal 66

67. Varenicline dosing Begin while the patient is still smoking
“Starter Pack”
Initial dose = 0.5 mg at breakfast x days 1-3
Then 0.5 breakfast and dinner x days 4-8
“Continuation Pack”
1 breakfast and dinner 67

68. Varenicline dosing
Since varenicline is a partial nicotine agonist, it is illogical to use a nicotine replacement product at the same time
There is inadequate data to advise for or against the simultaneous use of bupropion of nortriptyline for smoking cessation
Simultaneous use of antihypertensives, antidepressants, neuroleptics, and anticonvulsants appears safe 68

69. Effective Treatment Takes Time
WHAT YOUR PATIENT NEEDS TO HEAR FROM YOU – 1 (At the Start of Treatment)
Effective Treatment Takes Time
Mean: 6-9 months
Range: 6 weeks to many years
25-35% need lifetime treatment
Goals of Treatment
Stop smoking
Suppress nicotine withdrawal symptoms

70. Keep Communication Lines Open
WHAT YOUR PATIENT NEEDS TO HEAR FROM YOU -2 (At the Start of Treatment)
Goals of Tapering
Continue to be tobacco-free
Continue to blunt nicotine withdrawal symptoms
Thus: Medication Tapering is NOT a Down Escalator
Keep Communication Lines Open
Call me, your doctor, if you even think you may be having a problem

71. Thank you.